This is an application for a NIDA RSDA award. The primary focus of my research is to understand the mechanisms underlying the acute and chronic behavioral effects of cannabinoids (the principal psychoactive constituents of marijuana). My work is focused on the function and regulation of the neuronal cannabinoid receptor (CB1). Cannabinoids, acting at the CB1 receptor, are potent modulators of ion channel function. Specifically, they inhibit and Q-type voltage-dependent calcium channels and activate inwardly rectifying potassium channels. Consistent with these actions, cannabinoids decrease neuronal excitability and neurotransmission from CB1-expressing neurons. It is likely that these phenomena lead to the behavioral effects of cannabinoids. Over the next five years, we will continue our studies at the molecular and genetic level, emphasizing the following specific aims: * Is tolerance to cannabinoids in animals due to the phosphorylation and/or internalization of CB1 receptors? * Is the endogenous cannabinoid system necessary for the development of opiate tolerance? * What is the role of CB1 receptor dimerization in CB1 signaling and desensitization? * Are there CB1 and CB2 agonists that cause little or no desensitization of CB1 or CB2 receptor signaling? * Which domains of the potassium M current channel are important for its modulation by GPCR's? Accomplishing these goals will significantly advance our understanding of the cellular actions of cannabinoids. To accomplish these ambitious goals I have assembled a group of collaborators and consultants whose expertise complements that currently in place in my laboratory. Three facts underscore the importance of having a solid understanding of the CB1 receptor function at the molecular level: (1) Marijuana use is increasing and is a significant social issue. (2) Cannabinoids have therapeutic potential and we need a firm understanding of their cellular and chronic effects to understand the implications of their chronic use. (3) We know little about the physiological role of endogenous cannabinoids in healthy or diseased brain. Funding of this proposal will permit the investigator sufficient research time to accomplish the goal of elucidating the neuronal basis of cannabinoid action.